Cardiol Ther (2016) 5:85–100 DOI 10.1007/s40119-016-0061-7
ORIGINAL RESEARCH
Efficacy and Safety of Novel Oral Anticoagulants for Atrial Fibrillation Ablation: An Updated Meta-Analysis Ajay Vallakati . Abhishek Sharma . Mohammed Madmani . Madhu Reddy . Arun Kanmanthareddy . Sampath Gunda . Dhanunjaya Lakkireddy . William R. Lewis
Received: March 14, 2016 / Published online: April 22, 2016 Ó The Author(s) 2016. This article is published with open access at Springerlink.com
ABSTRACT
performing a meta-analysis of trials comparing
Introduction: Novel
NOACs with warfarin. Methods: Studies comparing
oral
anticoagulants
NOACs
(NOACs) have been approved for prevention
(dabigatran and rivaroxaban) with warfarin as
of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF). A
periprocedural anticoagulants for AF ablation were identified using an electronic search.
large number of patients are on NOACs when they present for AF ablation. We intended to
Primary outcomes were: (1) a composite endpoint of stroke, transient ischemic attack
evaluate the safety and efficacy of NOACs for AF
(TIA), peripheral arterial embolism, or silent
ablation during the periprocedural period by
cerebral lesions on magnetic resonance imaging (MRI) and (2) major bleeding complications. A
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random effects model was used to pool the safety and efficacy data across all included trials.
Electronic supplementary material The online version of this article (doi:10.1007/s40119-016-0061-7) contains supplementary material, which is available to authorized users. A. Vallakati M. Madmani W. R. Lewis Metrohealth Medical Center, Case Western Reserve University, Cleveland, OH, USA A. Sharma (&) Division of Cardiovascular Diseases, State University of New York, Downstate Medical Center, Brooklyn, NY, USA e-mail: [email protected] M. Reddy A. Kanmanthareddy S. Gunda D. Lakkireddy Division of Cardiovascular Diseases, Cardiovascular Research Institute, Mid America Cardiology, University of Kansas Hospital and Medical Center, Kansas City, KS, USA
Results: When compared to warfarin, there was an increased risk of the composite endpoint of stroke, TIA, peripheral arterial embolism, or silent cerebral lesions on MRI with NOACs as periprocedural anticoagulants for AF ablation [odds ratio (OR): 1.69, 95% confidence interval (CI): 1.06–2.68]. Sub-group analysis revealed a higher risk of composite endpoint with dabigatran as a periprocedural anticoagulant for AF ablation (OR: 2.01, 95% CI: 1.19–3.39) whereas the risk was similar with rivaroxaban (OR: 0.90, 95% CI: 0.34–2.41). Sensitivity analysis after excluding silent cerebral lesions on MRI showed there was no increased risk of
Cardiol Ther (2016) 5:85–100
86
thromboembolic events with either dabigatran
We performed a meta-analysis of trials comparing
(OR: 1.69, 95% CI: 0.81–3.51) or rivaroxaban (OR: 0.70, 95% CI: 0.12–4.04). Risk of bleeding
the safety and efficacy of NOACs with warfarin in
with NOACs was similar to warfarin (OR: 0.91, 95% CI: 0.62–1.34). Conclusion: NOACs are comparable to warfarin in terms of bleeding complications. However, dabigatran therapy is potentially associated with a higher risk of silent cerebral lesions on MRI. The results of this study should be considered
as
hypothesis-generating
and
assessed further in prospective randomized clinical studies. Keywords: Ablation;
Atrial
patients undergoing AF ablation.
METHODS We conducted a systematic review of published literature comparing NOACs with warfarin for AF ablation during the periprocedural period using Meta-Analysis of Observational Studies in Epidemiology (MOOSE) guidelines [14]. We searched PubMed, the Cochrane library and Embase for studies comparing NOACs (dabigatran, apixaban, and rivaroxaban) with
fibrillation;
warfarin as periprocedural anticoagulants for
Bleeding; Complications; Meta-analysis; Novel
RFA. The searches were extended from January 2009 to May 2014.
oral anticoagulants (NOACs); Thromboembolism
INTRODUCTION
We used search terms ‘‘dabigatran’’ AND ‘‘ablation’’, ‘‘rivaroxaban’’ AND ‘‘ablation’’, ‘‘apixaban’’ AND ‘‘ablation’’. Meeting abstracts
Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and is associated with an increased risk of mortality, heart failure, and thromboembolic events [1–3]. Warfarin reduces the risk of stroke in moderate to high-risk AF patients [4]. Novel oral anticoagulants (NOACs) have been approved for prevention of stroke and systemic embolism in patients with non-valvular AF (NVAF) [5–8]. Prevention of AF recurrence by radiofrequency ablation (RFA) is a well accepted therapeutic strategy in patients with symptomatic AF [9]. Given the increasing use of NOACs for stroke prevention in AF over the past few years, a large number of patients are already on NOACs when they present for AF ablation [10]. Few studies reported pooled data of safety and efficacy of NOACs as periprocedural anticoagulants for AF ablation [11–13]. To our knowledge, there is no pooled analysis addressing the risk of cerebral microthromboembolism with these procedures.
were searched in Embase. In the Cochrane database, search terms were limited by the term clinical trial. Limiting the search parameters to the English language was applied subsequently. Citations were screened at the title and abstract level and retrieved if they were either presented at conference or published as full reports, compared NOACs with warfarin, and provided information on the outcomes. The full texts of all potential articles were reviewed in detail. The bibliography of retained studies was used to seek additional relevant studies. All observational studies without a control group, case reports, editorials, pilot series, and reviews were excluded. Inclusion Criteria We included only studies that involved adult patients undergoing RFA alone and compared the outcomes with periprocedural anticoagulation with warfarin therapy (with or
Cardiol Ther (2016) 5:85–100
87
without heparin bridging) and NOACs. When
Statistical Analysis
two similar studies were reported from the same institution or author, the most recent publication was included in the analysis. Inclusion was not limited to prospective studies but was extended to all observational studies including retrospective studies.
We
performed
meta-analysis
of
primary
outcomes using a random effects model of the Mantel–Haenszel method. Odds ratio (OR) estimates and 95% confidence intervals (CI) were used to calculate the overall effect size of both outcomes. Statistical significance for OR
Exclusion Criteria
was set at P\0.05 (two-tailed) provided the CI did not cross. Heterogeneity was assessed by a v2
We excluded studies if outcomes of interest
and I2 test. Significant heterogeneity was considered present for P values \0.10 and an
were not clearly reported or were impossible to extract or calculate from the published results.
I2 C50%. Sensitivity analysis was performed by
Data Extraction
using a (1) fixed effects and random effects analysis (2) conducting a subgroup analysis
Data from included studies was extracted onto a pre-formed data extraction paper by two authors (AV, MM) independently. Data was then entered into Review Manager 5.2 for
(dabigatran vs. warfarin alone, rivaroxaban vs. warfarin) and (3) further subgroup analysis evaluating
symptomatic
thromboembolic
events. Data analysis was performed using RevMan version 5.2.
analysis. Data collected included first author, year and journal of publication, study design, inclusion/exclusion criteria, definition of
Compliance with Ethics Guidelines
primary and secondary end points, number of subjects included, study population
This article is based on previously conducted
demographics, anticoagulation agent used, type of procedure, and primary outcomes.
human or animal subjects performed by any of the authors.
Disagreement
between
the
reviewers
studies and does not involve any new studies of
was
resolved by discussion.
RESULTS
Study End Points
Using the search key words, we identified 637 papers, of which 29 studies (dabigatran 23,
Primary outcomes were: 1. A composite endpoint of stroke, transient
rivaroxaban
ischemic attack (TIA), peripheral arterial embolism, or silent cerebral lesions on magnetic resonance imaging (MRI) 2.
Major bleeding: 1. Bleeding requiring 2.
6)
were
selected
for
the
meta-analysis [15–41]. One study which compared NOACs with warfarin for both cardioversion and AF ablation was not included in the pooled analysis [42]. All studies included in the analysis were published
intervention/
hospitalization Significant pericardial effusion
between 2011 and 2014 (Fig. 1). Pooled analysis included 7671 patients, of whom 3220 (dabigatran 2629, rivaroxaban 591) were on
Cardiol Ther (2016) 5:85–100
88
NOACs and 4451 were on warfarin. The study
peripheral arterial embolism, or silent cerebral
characteristics
lesions on MRI with NOACs compared to
and
overall
patient
demographics are presented in Table 1.
warfarin when used for AF ablation (OR: 1.69, 95% CI: 1.06–2.68, P = 0.03; Fig. 3).
Composite Endpoint
Subgroup analysis of studies comparing dabigatran with warfarin for AF ablation
There was no significant heterogeneity among studies when assessed by v2 and I2 tests
showed that dabigatran increased the risk of the composite endpoint (OR: 2.01, 95% CI: 1.19–3.39, P = 0.009). Conversely, there was
analysis showed that there was an increased risk of the composite endpoint of stroke, TIA,
no difference in incidence of the composite endpoints between rivaroxaban and warfarin
Idenficaon
(v2 = 11.91; P = 0.94; I2 = 0%; Fig. 2). Pooled
Records idenfied using “dabigatran” AND “ablaon” (n = 333)
Records idenfied using “rivaroxaban” AND “ablaon” (n = 176)
Records idenfied “apixaban” AND “ablaon” (n = 128)
Eligibility
Screening
Records aer duplicates removed (n = 480)
Records screened (n = 480)
Full-text arcles / conference abstracts assessed for eligibility (n = 70)
Records excluded (n = 410)
Full-text arcles excluded (n = 41) No comparison group: 9 Meta-analysis: 13 Dabigatran vs rivaroxaban = 2 Same paent sample = 10 Others = 7
Included
Studies assessed qualitave synthesis (n = 29)
Studies included in quantave synthesis (meta-analysis) (n = 29)
Fig. 1 Preferred reporting items for systematic reviews and meta-analyses (PRISMA) flow sheet
Year
2013
2013
2013
2012
2013
2013
2013
2013
2013
2012
2013
Study
Arshad [15]
Bassiouny [16]
Bernard [17]
Ellis [18]
Gadiyaram [19]
Haines [20]
Ichiki [21]
Imamura [22]
Kaiser [23]
Kaseno [24]
Khan [25]
ACC
Circulation Journal
JICE
JICE
PACE
JICE
HRS
HRS
ACC
Circ EP
HRS
Publication/ meeting
50, 66
110, 101
122, 135
101, 126
30, 180
202, 202
54, 128
56.3, -
–
58, 64
61, 62
57, 60
60.2, 59.7
62.7
–
(63, 63)b, 67
(155, 75)b, 44 61, 110
59, 63
60.7 ± 10
Mean age [years; (NOACs, W)]
376, 623
298, 153
Sample size (NOACs, W)
Table 1 Characteristics of included studies
39
–
36, 32
25, 30
17, 22
26, 31
24, 24
–
–
25, 27
28
Females,% (NOACs, W)
–
–
69, 47
44, 51
70, 30
55, 50
–
–
(46, 57)b, 50
Abl.
Abl.
LAA abl.
Abl.
Abl.
Abl.
Abl.
Abl.
Abl.
Abl.
Abl.
67a
57, 55
Type of procedure
PAF (%; NOACs, W)
1.06, -
–
1.2 ± 1, 1.6 ± 1
0.9 ± 0.9, 1.1 ± 1.0
1.1 ± 1.1, 1.0 ± 1.0
1.6 ± 1.3, 1.9 ± 1.4c
–
1.2 ± 0.2
–
–
1.3 ± 1.0
CHADS2 score (NOACs, W)
–
–
–
0.7 ± 0.8, 1.0 ± 0.9
–
–
–
–
–
–
2.8 ± 1.0
HAS-BLED score (NOACs, W)
D 150
D 110
D 150
D 110/D 150 depending on patient’s condition
D 110–13 patients, D 150–17
D 150 (1 patient received D 110)
R
D 150, R
D 150, R
D 150
D 150
NOACs: drug, dose (mg)
Warfarin was stopped 3 days before the procedure and unfractionated heparin was administered Held 12–24 h before and restarted 3 h after the procedure
Last dose held 24 h prior to the procedure and restarted 6 h after sheath removal
Held on the morning of the procedure, and resumed on the next morning
Uninterrupted
Uninterrupted
Uninterrupted
Uninterrupted Discontinued only on the morning of the procedure, resumed from the evening
Held 24–30 h pre-procedure and restarted 4–6 h after hemostasis was achieved
Therapeutic pre-procedure INR in 80%, remaining bridged with lovenox
Uninterrupted
Subtherapeutic INR bridged with heparin
Uninterrupted
Uninterrupted
Uninterrupted
Warfarin
17% received D within 12 h before the procedure, D resumed within 24 h
Held 2 days before ablation, one dose of lovenox 6 h after hemostasis was achieved and R was resumed the next day
Held 12–48 h pre-procedure, resumed within 4–24 h after sheath pull
Held within 24 h pre-procedure and restarted within 24 h post-procedure
1–2 doses held before procedure resumed at conclusion of the procedure
Held 12 h pre-procedure and resumed on post-procedure night
NOACs held
Cardiol Ther (2016) 5:85–100 89
2013
Nin [31]
2014
2013
Mohajer [30]
Snipelisky [41]
2012
Mendoza [29]
2012
2013
Maddox [28]
Snipelisky [32]
2014
Lakkireddy [38]
2012
2013
Lakkireddy [27]
2012
2012
Konduru [37]
Pavaci [39]
2013
Kim [26]
Rowley [40]
Year
Study
HRS
JICE
HRS
ESC
PACE
Canadian Journal of Cardiology
HRS
JCE
JACC
JACC
JICE
Heart Rhythm
Publication/ meeting
Table 1 continued
27, 27
56, 25, 48
31, 125
113, 169
–
60.6, 64.6
63
–
61, 61
60, 63
43, 95
45, 45
62.9, 64.0
62.3, 62.5
63, 63
60.4, 60.3
56.6, 60.9
61, 61
Mean age [years; (NOACs, W)]
60, 58
212, 251
321, 321
145, 145
24, 52
191, 572
Sample size (NOACs, W)
–
19.4, 25.6
–
–
16, 20
–
10, 12
24, 33
31, 31
21, 21
21, 33
20, 26
Females,% (NOACs, W)
–
68, 46
–
–
34, 32
69.8, 41.1
63, 57
49, 49
57, 57
21, 44
53, 48
PAF (%; NOACs, W)
Abl.
Abl.
Abl.
Abl.
Abl.
Abl.
Abl.
Abl.
Abl.
Abl.
Abl.
Abl.
Type of procedure
–
0.84, 1.22
1.3 ± 1
–
–
0.6 ± 0.7, 0.9 ± 0.9
1.32, 1.29
0.92 ± 0.88, 0.92 ± 0.85
1.16 ± 1.0, 1.18 ± 1.0
1.6 ± 1.4, 1.5 ± 1.3c
–
1.0 ± 0.9, 1.1 ± 1.0
CHADS2 score (NOACs, W)
–
–
–
–
–
–
1.47, 1.63
1.47 ± 0.9, 1.70 ± 1.0
1.2 ± 0.9, 1.1 ± 0.9
–
1.0 ± 0.9, 1.1 ± 1.0
HAS-BLED score (NOACs, W)
D, R
D 150
–
–
D 110
D 150 (D 110 in 3 patients)
D 150
D 150
R 15, 20
D 150
D 150
D 150
NOACs: drug, dose (mg)
–
–
Held the dose on the morning of the procedure
Last dose the day before AF ablation and typically restarted the day following ablation
–
Uninterrupted
Bridged with enoxaparin
–
Uninterrupted
Uninterrupted
Held 24 h prior to procedure
Held on morning of the procedure and resumed 4 h after hemostasis
Uninterrupted
Uninterrupted
Uninterrupted
Uninterrupted
Uninterrupted
Uninterrupted
Warfarin
Held only the morning of the procedure and resumed immediately after sheath removal
Morning dose on the day of the ablation procedure; post-procedural dabigatran was administered on the evening of the procedure
Uninterrupted
Held on the morning of the procedure, resumed within 3 h after hemostasis
Continued without interruption (first 11 patients) or held 2 doses immediately prior to the procedure (last 13 patients). D was continued the evening following the procedure
Held after the morning dose on the day before the procedure and resumed 4 h after hemostasis was achieved
NOACs held
90 Cardiol Ther (2016) 5:85–100
Clinical Drug Inv.
106, 106
79, 15, 45
70, 70
89, 98, 114
Sample size (NOACs, W)
60, 61
61
66
59, 60, 62.9
Mean age [years; (NOACs, W)]
25, 24
25
30
42, 34, 33
Females,% (NOACs, W)
65, 64
–
73
70, 81, 64
PAF (%; NOACs, W)
Abl.
Abl.
Abl.
Abl.
Type of procedure
1.8 ± 1.6, 1.7 ± 1.6
–
–
–
CHADS2 score (NOACs, W)
–
–
–
–
HAS-BLED score (NOACs, W)
D 110 (36), D 150 (70)
D, R
R 10, 15
D, R
NOACs: drug, dose (mg)
– Uninterrupted
Held on the day of procedure, resumed 3 h after the completion
Uninterrupted
Uninterrupted
Warfarin
–
Uninterrupted
The last dose of D was given the morning 1 day prior to the procedure, and the last dose of R was given the evening 2 days prior. Bridged with heparin NOAC was resumed at 8:00 a.m. on the morning after the procedure
NOACs held
a
Abl. ablation, ACC American College of Cardiology, D dabigatran, ESC European Society of Cardiology, HRS Heart Rhythm Society, INR international normalized ratio, NOACs novel oral anticoagulants, PAF paroxysmal atrial fibrillation, R rivaroxaban, W warfarin Total PAF in study cohort b NOACs (dabigatran, rivaroxaban) c CHADS2-Vasc score
2013
Yamaji [36]
HRS
HRS
2014
2014
Tao [34]
Ueno [35]
JICE
2014
Stepanyan [33]
Publication/ meeting
Year
Study
Table 1 continued
Cardiol Ther (2016) 5:85–100 91
Cardiol Ther (2016) 5:85–100
92
Fig. 2 Funnel plot to assess publication bias for a the composite endpoint of stroke, TIA, peripheral arterial embolism, or silent cerebral lesions on MRI b major bleeding for AF ablation (OR: 0.90, 95% CI: 0.34–2.41, P = 0.84). Sensitivity analysis was performed by
Exclusion sensitivity analysis including only symptomatic thromboembolic complications
using a fixed effects analysis method. Effect size
(stroke, TIA, and peripheral arterial embolism)
did not change with fixed effects analysis. To assess whether the time of holding NOAC
was performed after omitting studies reporting silent cerebral lesions on MRI. Sensitivity
affected the composite endpoint, exclusion sensitivity analysis was performed by
analysis did not reveal any difference between NOACs and warfarin (OR: 1.48, 95% CI:
including only those studies in which an
0.75–2.91, P = 0.25; Fig. 4). Subgroup analysis
NOAC was held on the day of AF ablation. This analysis showed that dabigatran was
did not show any increased risk with either dabigatran or rivaroxaban for AF ablation (OR:
associated with increased risk of the composite endpoint (OR: 2.40, 95% CI: 1.10–5.22,
1.69, 95% CI: 0.81–3.51, P = 0.16 and OR: 0.70, 95% CI: 0.12–4.04, P = 0.69, respectively;
P = 0.03).
Fig. 4).
On
the
other
hand,
use
of
rivaroxaban did not increase the risk of thromboembolic complications (OR: 1.1, 95% CI 0.30–4.79, P = 0.79). In four studies [18, 20, 22, 40], heparin was used for bridging during the periprocedural period for anticoagulation. To assess whether uninterrupted warfarin affected the composite endpoint, sensitivity analysis was conducted by omitting studies in which heparin bridging was used. Pooled analysis of the remaining studies revealed that dabigatran was associated with increased risk of the composite endpoint (OR: 1.81, 95% CI: 1.02–3.19, P = 0.04) whereas rivaroxaban therapy did not increase the risk of thromboembolic complications (OR: 0.90, 95% CI: 0.34–2.41, P = 0.84).
Major Bleeding There was no significant heterogeneity across the studies (v2 = 23, degrees of freedom = 23; P = 0.46; I2 = 0%). Major bleeding events were similar with NOACs and warfarin for AF ablation (OR: 0.91, 95% CI: 0.62–1.34, P = 0.63; Fig. 5). Pooled analysis of studies in which uninterrupted warfarin was utilized for periprocedural anticoagulation did not show any significant difference in major bleeding between NOACs and warfarin (OR: 0.93, 95% CI: 0.58–1.50, P = 0.77).
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Fig. 3 Forest plot showing sub group analysis of the composite endpoint of stroke, TIA, peripheral arterial embolism, or silent cerebral lesions on MRI based on type of new oral anticoagulants
Major Bleeding-Type of NOACs Subgroup analysis, based on the type of NOAC, revealed similar major bleeding with dabigatran and warfarin when used for AF ablation (OR:
0.99, 95% CI: 0.62–1.57, P = 0.96). There was no significance difference in major bleeding between rivaroxaban and warfarin (OR: 0.60, 95% CI: 0.25–1.45, P = 0.25).
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Fig. 4 Forest plot showing sub group analysis of symptomatic thromboembolic events (stroke, TIA, and peripheral arterial embolism) based on type of new oral anticoagulants
DISCUSSION
embolism, or silent cerebral lesions on MRI compared to warfarin. However, the risk of
There are three major findings of this study. First, the use of dabigatran for periprocedural
symptomatic
thromboembolic
events
with
anticoagulation for AF ablation is associated
dabigatran therapy anticoagulation with
is similar to warfarin. Second,
with an increased risk of the composite endpoint of stroke, TIA, peripheral arterial
rivaroxaban is not associated with increased risk of the composite endpoint when compared
Cardiol Ther (2016) 5:85–100
95
Fig. 5 Forest plot showing sub group analysis of bleeding events based on type of new oral anticoagulants to warfarin. Third, dabigatran and rivaroxaban are comparable to warfarin in terms of bleeding
Rhythm Society (HRS) guidelines recommend anticoagulation in patients with AF with high
complications.
risk for thromboembolic events identified by
Current American Heart Association (AHA)/ American College of Cardiology (ACC)/Heart
the CHA2DS2-VASc score [43]. Recent meta-analyses presented mixed data regarding
Cardiol Ther (2016) 5:85–100
96
the
role
of
dabigatran
therapy
for
sample size of the rivaroxaban subgroup (548
periprocedural anticoagulation for AF ablation
vs. 2451 in the dabigatran subgroup).
[11–13, 44]. Our study suggests dabigatran therapy for AF ablation may be associated with
Silent cerebral infarcts may be associated with neurocognitive impairment and/or gait
increased thromboembolic risk. Shurrab et al. [12] and Bin Abdulhak et al. [44] reported no
abnormality [47]. A recent retrospective study evaluating the incidence of silent cerebral
significant difference in thromboembolic events
lesions
between dabigatran and warfarin therapy. Sardar et al. [11] and Steinberg et al. [13]
edoxaban suggested an increased risk of silent cerebral lesions with dabigatran [48]. This is
observed that periprocedural dabigatran use may be associated with increased risk of
consistent with the findings of our study, which showed potentially higher risk of silent cerebral
neurological events. In these meta-analyses,
lesions with dabigatran. The majority (91.8%)
silent cerebral lesions on MRI were not included as one of the primary outcomes. Our
of the cerebral lesions noted on initial MRI were not seen on following MRI suggesting that only
study is the first pooled analysis to include and evaluate the incidence of silent cerebral lesions
a few lesions develop into chronic cerebral lesions [48]. This study was limited by the
on MRI. Gaita et al. [45] reported an incidence
retrospective and non-randomized nature of
of cerebral microthromboembolism of 14% with warfarin therapy for AF ablation and
the study. Prospective randomized clinical studies are needed to evaluate the incidence of
increased risk of cerebrovascular events was related to use of cardioversion. Our pooled
cerebral microthromboembolism with NOACs and to determine clinical characteristics which
analysis included silent cerebral lesions on MRI as one of the primary outcomes and it
increase the likelihood microthromboembolism.
revealed that dabigatran therapy is potentially
Our
with
study
different
is
NOACs
consistent
including
of
cerebral
with
other
associated with a higher risk of silent cerebral lesions on MRI. Exclusion sensitivity analysis
meta-analyses which revealed NOACs are associated with similar bleeding risk when
after omitting studies reporting silent cerebral lesions on MRI did not show any significant
compared to warfarin [11–13, 44]. Subgroup analysis based on type of anticoagulant did not
difference in thromboembolic events between
show any difference between the NOACs.
dabigatran and warfarin therapy for AF ablation. Ueno et al. [46] showed that during
Limitations
AF ablation, pro-thrombotic factors are activated more with dabigatran than warfarin.
The studies included in the meta-analysis had
Ichiki et al. [21] observed an increased risk of asymptomatic cerebral thromboembolic events with dabigatran therapy for AF ablation.
differences in their study protocol. We could not study the risk of thromboembolic and bleeding events based on the dose of NOACs
Conversely, Kaseno et al. [24] reported similar cerebral microthromboembolism with
(110, 150 mg of dabigatran; 10, 15, 20 mg of rivaroxaban). There was significant
dabigatran. Our analysis did not show any
heterogeneity in different protocols in terms of number of doses of NOACs held prior to the
difference in the composite endpoints between rivaroxaban and warfarin therapy for AF ablation. This analysis may be limited by small
ablation, bridging therapy with heparin, and timing of resumption of NOACs after the
Cardiol Ther (2016) 5:85–100
97
procedure. Definitions for safety and efficacy
William R. Lewis have no conflict of interest
outcomes, and baseline characteristics of the
relevant to the topic in discussion.
patients varied across the studies. The majority of the studies were observational studies without any randomization or propensity matching. Apixaban is being increasingly used in clinical practice for AF ablation. Studies evaluating the safety and efficacy of periprocedural anticoagulation with apixaban and edoxaban for AF ablation were not included in the pooled analysis [48–50] as these studies were published after the completion of the literature search in May 2014.
Compliance with Ethics Guidelines. This article
is
based
on
previously
conducted
studies and does not involve any new studies of human or animal subjects performed by any of the authors. Open Access. This article is distributed under the terms of the Creative Commons AttributionNonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4. 0/), which permits any noncommercial use, distribution, and reproduction in any medium,
CONCLUSIONS
provided you give appropriate credit to the
Dabigatran and rivaroxaban are comparable to
original author(s) and the source, provide a link to the Creative Commons license, and indicate
warfarin in terms of bleeding complications. However, dabigatran therapy is potentially
if changes were made.
associated with a higher risk of cerebral lesions on MRI. The results of study should be considered as hypothesis-generating and
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3.
Chugh SS, Blackshear JL, Shen WK, Hammill SC, Gersh BJ. Epidemiology and natural history of atrial fibrillation: clinical implications. J Am Coll Cardiol. 2001;37:371–8.
4.
Singer DE, Chang Y, Fang MC, et al. The net clinical benefit of warfarin anticoagulation in atrial fibrillation. Ann Intern Med. 2009;151:297–305.
5.
Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361:1139–51.
6.
Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365:883–91.
No funding or sponsorship was received for this study or publication of this article. All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval for the version to be published. Disclosures. Dhanunjaya
Lakkireddy
has
received modest speaker’s honorarium from Boehringer Ingelheim. Ajay Vallakati, Abhishek Sharma, Mohammed Madmani, Madhu Reddy, Arun Kanmanthareddy, Sampath Gunda, and
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8.
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9.
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10. Kirley K, Qato DM, Kornfield R, Stafford RS, Alexander GC. National trends in oral anticoagulant use in the United States, 2007 to 2011. Circ Cardiovasc Qual Outcomes. 2012;5:615–21. 11. Sardar P, Nairooz R, Chatterjee S, Wetterslev J, Ghosh J, Aronow WS. Meta-analysis of risk of stroke or transient ischemic attack with dabigatran for atrial fibrillation ablation. Am J Cardiol. 2014;113:1173–7. 12. Shurrab M, Morillo CA, Schulman S, et al. Safety and efficacy of dabigatran compared with warfarin for patients undergoing radiofrequency catheter ablation of atrial fibrillation: a meta-analysis. Can J Cardiol. 2013;29:1203–10. 13. Steinberg BA, Hasselblad V, Atwater BD, et al. Dabigatran for periprocedural anticoagulation following radiofrequency ablation for atrial fibrillation: a meta-analysis of observational studies. J Interv Cardiac Electrophysiol Int J Arrhythm Pacing. 2013;37:213–21. 14. Stroup DF, Berlin JA, Morton SC, et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA J Am Med Assoc. 2000;283:2008–12. 15. Arshad A, Buch E, Hamam I, et al. Comparative safety of anticoagulation strategies peri-ablation for atrial fibrillation: data from a large multicenter study. Heart Rhythm. 2013;10:S74. 16. Bassiouny M, Saliba W, Rickard J, et al. Use of dabigatran for periprocedural anticoagulation in patients undergoing catheter ablation for atrial fibrillation. Circ Arrhythm Electrophysiol. 2013;6:460–4. 17. Bernard M, Brabham W, Netzler P, et al. Comparison of atrial fibrillation ablation bleeding and thrombotic complications with dabigatran,
rivaroxaban and warfarin. J Am Coll Cardiol. 2013;61:E276. 18. Ellis CR, Streur MM, Nagarakanti R. Safety and efficacy of dabigatran versus warfarin in patients undergoing left atrial catheter ablation. Heart Rhythm. 2012;9:S421. 19. Gadiyaram VK, Boero I, Kawata H, et al. Rivaroxaban has similar safety and efficacy as warfarin for peri-procedural anticoagulation for atrial fibrillation ablation. Heart Rhythm. 2013;10:S142–3. 20. Haines DE, Mead-Salley M, Salazar M, et al. Dabigatran versus warfarin anticoagulation before and after catheter ablation for the treatment of atrial fibrillation. J Interv Cardiac Electrophysiol. 2013;37:233–9. 21. Ichiki H, Oketani N, Ishida S, et al. The incidence of asymptomatic cerebral microthromboembolism after atrial fibrillation ablation: comparison of warfarin and dabigatran. PACE Pacing Clin Electrophysiol. 2013;36:1328–35. 22. Imamura K, Yoshida A, Takei A, et al. Dabigatran in the peri-procedural period for radiofrequency ablation of atrial fibrillation: efficacy, safety, and impact on duration of hospital stay. J Interv Cardiac Electrophysiol. 2013;37:223–31. 23. Kaiser DW, Streur MM, Nagarakanti R, Whalen SP, Ellis CR. Continuous warfarin versus periprocedural dabigatran to reduce stroke and systemic embolism in patients undergoing catheter ablation for atrial fibrillation or left atrial flutter. J Interv Cardiac Electrophysiol. 2013;37:241–7. 24. Kaseno K, Naito S, Nakamura K, et al. Efficacy and safety of periprocedural dabigatran in patients undergoing catheter ablation of atrial fibrillation. Circ J. 2012;76:2337–42. 25. Khan S, Duggal M, Dunskis P, Bhan A. Periprocedural dabigatran in patients undergoing catheter ablation for at rial fibrillation. J Am Coll Cardiol. 2013;61:E401. 26. Kim JS, She F, Jongnarangsin K, et al. Dabigatran vs warfarin for radiofrequency catheter ablation of atrial fibrillation. Heart Rhythm. 2013;10:483–9. 27. Lakkireddy D, Reddy YM, Di Biase L, et al. Feasibility and safety of uninterrupted rivaroxaban for periprocedural anticoagulation in patients undergoing radiofrequency ablation for atrial fibrillation: results from a multicenter prospective registry. J Am Coll Cardiol. 2014;63:982–8. 28. Maddox W, Kay GN, Yamada T, et al. Dabigatran versus warfarin therapy for uninterrupted oral
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anticoagulation during atrial fibrillation ablation. J Cardiovasc Electrophysiol. 2013;24:861–5. 29. Mendoza I, Helguera M, Baez-Escudero J, Reina J, Pinski SL. Atrial fibrillation ablation on uninterrupted anticoagulation with dabigatran versus warfarin. Heart Rhythm. 2012;9:S270–1. 30. Mohajer K, Haley C, Simpson C, et al. Comparison of dabigatran and conventional anticoagulation practices in patients undergoing elective left atrial ablation. Can J Cardiol. 2013;29:S184. 31. Nin T, Sairaku A, Yoshida Y, et al. A randomized controlled trial of dabigatran versus warfarin for periablation anticoagulation in patients undergoing ablation of atrial fibrillation. PACE Pacing Clin Electrophysiol. 2013;36:172–9. 32. Snipelisky D, Ray J, Ung R, Duart M, Kauffman C, Kusumoto F. A comparison of bleeding complications between warfarin and dabigatran in patients undergoing cryoablation. Heart Rhythm. 2014;11:S456–7. 33. Stepanyan G, Badhwar N, Lee RJ, et al. Safety of new oral anticoagulants for patients undergoing atrial fibrillation ablation. J Interv Cardiac Electrophysiol. 2014;40:33–8. 34. Tao S, Kenichiro O, Yuichi O, et al. Efficacy and safety of rivaroxaban versus warfarin as uninterrupted anticoagulation for radiofrequency catheter ablation of atrial fibrillation. Heart Rhythm. 2014;11:S228. 35. Ueno A, Morita N, Iida T, Fujibayashi D, Kobayashi Y. Evaluation of peri-procedural coagulation status of atrial fibrillation ablation; impact of different anticoagulants on the risk of silent cerebral infarction. Heart Rhythm. 2014;11:S395. 36. Yamaji H, Murakami T, Hina K, et al. Usefulness of dabigatran etexilate as periprocedural anticoagulation therapy for atrial fibrillation ablation. Clin Drug Investig. 2013;33:409–18. 37. Konduru SV, Cheema AA, Jones P, Li Y, Ramza B, Wimmer AP. Differences in intraprocedural ACTs with standardized heparin dosing during catheter ablation for atrial fibrillation in patients treated with dabigatran vs. patients on uninterrupted warfarin. J Interv Cardiac Electrophysiol. 2012;35:277–84. 38. Lakkireddy D, Reddy YM, Di Biase L, et al. Feasibility and safety of dabigatran versus warfarin for periprocedural anticoagulation in patients undergoing radiofrequency ablation for atrial fibrillation: results from a multicenter prospective registry. J Am Coll Cardiol. 2012;59:1168–74.
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39. Pavaci H, Reents T, Ammar S, et al. Safety and efficacy of dabigatran in patients undergoing left atrial ablation procedures: a case matched analysis. Eur Heart J. 2012;33:60–1. 40. Rowley CP, Bradford NS, Bernard ML, et al. Complications of atrial fibrillation ablation in patients anticoagulated with dabigatran compared to warfarin. Heart Rhythm. 2012;9:S201. 41. Snipelisky D, Kauffman C, Kusumoto F. A comparison of bleeding complications post ablation between warfarin and dabigatran. Heart Rhythm. 2012;9:S203. 42. Piccini JP, Stevens SR, Lokhnygina Y, et al. Outcomes after cardioversion and atrial fibrillation ablation in patients treated with rivaroxaban and warfarin in the ROCKET AF Trial. J Am Coll Cardiol. 2013;61:1998–2006. 43. Anderson JL, Halperin JL, Albert NM, et al. Management of patients with atrial fibrillation (compilation of 2006 ACCF/AHA/ESC and 2011 ACCF/AHA/HRS recommendations): a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013;61:1935–44. 44. Bin Abdulhak AA, Khan AR, Tleyjeh IM, et al. Safety and efficacy of interrupted dabigatran for peri-procedural anticoagulation in catheter ablation of atrial fibrillation: a systematic review and meta-analysis. Europace Eur Pacing Arrhythm Cardiac Electrophysiol J Work Groups Cardiac Pacing Arrhythm Cardiac Cell Electrophysiol Eur Soc Cardiol. 2013;15:1412–20. 45. Gaita F, Caponi D, Pianelli M, et al. Radiofrequency catheter ablation of atrial fibrillation: a cause of silent thromboembolism? Magnetic resonance imaging assessment of cerebral thromboembolism in patients undergoing ablation of atrial fibrillation. Circulation. 2010;122:1667–73. 46. Ueno A, Morita N, Iida T, Fujibayashi D, Kobayashi Y. Comparison of coagulation status using dabigatran with warfarin for periprocedural anticoagulation during atrial fibrillation ablation procedure. Heart Rhythm. 2013;10:S384. 47. Fanning JP, Wesley AJ, Wong AA, Fraser JF. Emerging spectra of silent brain infarction. Stroke J Cereb Circ 2014;45:3461–3471. 48. Nakamura K, Naito S, Sasaki T, et al. Silent cerebral ischemic lesions after catheter ablation of atrial fibrillation in patients on 5 types of periprocedural oral anticoagulation-predictors of diffusion-weighted imaging-positive lesions and follow-up magnetic resonance imaging. Circ J Off J Jpn Circ Soc. 2016;80:870–7.
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ORIGINAL RESEARCH
Efficacy and Safety of Novel Oral Anticoagulants for Atrial Fibrillation Ablation: An Updated Meta-Analysis Ajay Vallakati . Abhishek Sharma . Mohammed Madmani . Madhu Reddy . Arun Kanmanthareddy . Sampath Gunda . Dhanunjaya Lakkireddy . William R. Lewis
Received: March 14, 2016 / Published online: April 22, 2016 Ó The Author(s) 2016. This article is published with open access at Springerlink.com
ABSTRACT
performing a meta-analysis of trials comparing
Introduction: Novel
NOACs with warfarin. Methods: Studies comparing
oral
anticoagulants
NOACs
(NOACs) have been approved for prevention
(dabigatran and rivaroxaban) with warfarin as
of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF). A
periprocedural anticoagulants for AF ablation were identified using an electronic search.
large number of patients are on NOACs when they present for AF ablation. We intended to
Primary outcomes were: (1) a composite endpoint of stroke, transient ischemic attack
evaluate the safety and efficacy of NOACs for AF
(TIA), peripheral arterial embolism, or silent
ablation during the periprocedural period by
cerebral lesions on magnetic resonance imaging (MRI) and (2) major bleeding complications. A
Enhanced content To view enhanced content for this article go to http://www.medengine.com/Redeem/47B 4F06014C4DF95.
random effects model was used to pool the safety and efficacy data across all included trials.
Electronic supplementary material The online version of this article (doi:10.1007/s40119-016-0061-7) contains supplementary material, which is available to authorized users. A. Vallakati M. Madmani W. R. Lewis Metrohealth Medical Center, Case Western Reserve University, Cleveland, OH, USA A. Sharma (&) Division of Cardiovascular Diseases, State University of New York, Downstate Medical Center, Brooklyn, NY, USA e-mail: [email protected] M. Reddy A. Kanmanthareddy S. Gunda D. Lakkireddy Division of Cardiovascular Diseases, Cardiovascular Research Institute, Mid America Cardiology, University of Kansas Hospital and Medical Center, Kansas City, KS, USA
Results: When compared to warfarin, there was an increased risk of the composite endpoint of stroke, TIA, peripheral arterial embolism, or silent cerebral lesions on MRI with NOACs as periprocedural anticoagulants for AF ablation [odds ratio (OR): 1.69, 95% confidence interval (CI): 1.06–2.68]. Sub-group analysis revealed a higher risk of composite endpoint with dabigatran as a periprocedural anticoagulant for AF ablation (OR: 2.01, 95% CI: 1.19–3.39) whereas the risk was similar with rivaroxaban (OR: 0.90, 95% CI: 0.34–2.41). Sensitivity analysis after excluding silent cerebral lesions on MRI showed there was no increased risk of
Cardiol Ther (2016) 5:85–100
86
thromboembolic events with either dabigatran
We performed a meta-analysis of trials comparing
(OR: 1.69, 95% CI: 0.81–3.51) or rivaroxaban (OR: 0.70, 95% CI: 0.12–4.04). Risk of bleeding
the safety and efficacy of NOACs with warfarin in
with NOACs was similar to warfarin (OR: 0.91, 95% CI: 0.62–1.34). Conclusion: NOACs are comparable to warfarin in terms of bleeding complications. However, dabigatran therapy is potentially associated with a higher risk of silent cerebral lesions on MRI. The results of this study should be considered
as
hypothesis-generating
and
assessed further in prospective randomized clinical studies. Keywords: Ablation;
Atrial
patients undergoing AF ablation.
METHODS We conducted a systematic review of published literature comparing NOACs with warfarin for AF ablation during the periprocedural period using Meta-Analysis of Observational Studies in Epidemiology (MOOSE) guidelines [14]. We searched PubMed, the Cochrane library and Embase for studies comparing NOACs (dabigatran, apixaban, and rivaroxaban) with
fibrillation;
warfarin as periprocedural anticoagulants for
Bleeding; Complications; Meta-analysis; Novel
RFA. The searches were extended from January 2009 to May 2014.
oral anticoagulants (NOACs); Thromboembolism
INTRODUCTION
We used search terms ‘‘dabigatran’’ AND ‘‘ablation’’, ‘‘rivaroxaban’’ AND ‘‘ablation’’, ‘‘apixaban’’ AND ‘‘ablation’’. Meeting abstracts
Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and is associated with an increased risk of mortality, heart failure, and thromboembolic events [1–3]. Warfarin reduces the risk of stroke in moderate to high-risk AF patients [4]. Novel oral anticoagulants (NOACs) have been approved for prevention of stroke and systemic embolism in patients with non-valvular AF (NVAF) [5–8]. Prevention of AF recurrence by radiofrequency ablation (RFA) is a well accepted therapeutic strategy in patients with symptomatic AF [9]. Given the increasing use of NOACs for stroke prevention in AF over the past few years, a large number of patients are already on NOACs when they present for AF ablation [10]. Few studies reported pooled data of safety and efficacy of NOACs as periprocedural anticoagulants for AF ablation [11–13]. To our knowledge, there is no pooled analysis addressing the risk of cerebral microthromboembolism with these procedures.
were searched in Embase. In the Cochrane database, search terms were limited by the term clinical trial. Limiting the search parameters to the English language was applied subsequently. Citations were screened at the title and abstract level and retrieved if they were either presented at conference or published as full reports, compared NOACs with warfarin, and provided information on the outcomes. The full texts of all potential articles were reviewed in detail. The bibliography of retained studies was used to seek additional relevant studies. All observational studies without a control group, case reports, editorials, pilot series, and reviews were excluded. Inclusion Criteria We included only studies that involved adult patients undergoing RFA alone and compared the outcomes with periprocedural anticoagulation with warfarin therapy (with or
Cardiol Ther (2016) 5:85–100
87
without heparin bridging) and NOACs. When
Statistical Analysis
two similar studies were reported from the same institution or author, the most recent publication was included in the analysis. Inclusion was not limited to prospective studies but was extended to all observational studies including retrospective studies.
We
performed
meta-analysis
of
primary
outcomes using a random effects model of the Mantel–Haenszel method. Odds ratio (OR) estimates and 95% confidence intervals (CI) were used to calculate the overall effect size of both outcomes. Statistical significance for OR
Exclusion Criteria
was set at P\0.05 (two-tailed) provided the CI did not cross. Heterogeneity was assessed by a v2
We excluded studies if outcomes of interest
and I2 test. Significant heterogeneity was considered present for P values \0.10 and an
were not clearly reported or were impossible to extract or calculate from the published results.
I2 C50%. Sensitivity analysis was performed by
Data Extraction
using a (1) fixed effects and random effects analysis (2) conducting a subgroup analysis
Data from included studies was extracted onto a pre-formed data extraction paper by two authors (AV, MM) independently. Data was then entered into Review Manager 5.2 for
(dabigatran vs. warfarin alone, rivaroxaban vs. warfarin) and (3) further subgroup analysis evaluating
symptomatic
thromboembolic
events. Data analysis was performed using RevMan version 5.2.
analysis. Data collected included first author, year and journal of publication, study design, inclusion/exclusion criteria, definition of
Compliance with Ethics Guidelines
primary and secondary end points, number of subjects included, study population
This article is based on previously conducted
demographics, anticoagulation agent used, type of procedure, and primary outcomes.
human or animal subjects performed by any of the authors.
Disagreement
between
the
reviewers
studies and does not involve any new studies of
was
resolved by discussion.
RESULTS
Study End Points
Using the search key words, we identified 637 papers, of which 29 studies (dabigatran 23,
Primary outcomes were: 1. A composite endpoint of stroke, transient
rivaroxaban
ischemic attack (TIA), peripheral arterial embolism, or silent cerebral lesions on magnetic resonance imaging (MRI) 2.
Major bleeding: 1. Bleeding requiring 2.
6)
were
selected
for
the
meta-analysis [15–41]. One study which compared NOACs with warfarin for both cardioversion and AF ablation was not included in the pooled analysis [42]. All studies included in the analysis were published
intervention/
hospitalization Significant pericardial effusion
between 2011 and 2014 (Fig. 1). Pooled analysis included 7671 patients, of whom 3220 (dabigatran 2629, rivaroxaban 591) were on
Cardiol Ther (2016) 5:85–100
88
NOACs and 4451 were on warfarin. The study
peripheral arterial embolism, or silent cerebral
characteristics
lesions on MRI with NOACs compared to
and
overall
patient
demographics are presented in Table 1.
warfarin when used for AF ablation (OR: 1.69, 95% CI: 1.06–2.68, P = 0.03; Fig. 3).
Composite Endpoint
Subgroup analysis of studies comparing dabigatran with warfarin for AF ablation
There was no significant heterogeneity among studies when assessed by v2 and I2 tests
showed that dabigatran increased the risk of the composite endpoint (OR: 2.01, 95% CI: 1.19–3.39, P = 0.009). Conversely, there was
analysis showed that there was an increased risk of the composite endpoint of stroke, TIA,
no difference in incidence of the composite endpoints between rivaroxaban and warfarin
Idenficaon
(v2 = 11.91; P = 0.94; I2 = 0%; Fig. 2). Pooled
Records idenfied using “dabigatran” AND “ablaon” (n = 333)
Records idenfied using “rivaroxaban” AND “ablaon” (n = 176)
Records idenfied “apixaban” AND “ablaon” (n = 128)
Eligibility
Screening
Records aer duplicates removed (n = 480)
Records screened (n = 480)
Full-text arcles / conference abstracts assessed for eligibility (n = 70)
Records excluded (n = 410)
Full-text arcles excluded (n = 41) No comparison group: 9 Meta-analysis: 13 Dabigatran vs rivaroxaban = 2 Same paent sample = 10 Others = 7
Included
Studies assessed qualitave synthesis (n = 29)
Studies included in quantave synthesis (meta-analysis) (n = 29)
Fig. 1 Preferred reporting items for systematic reviews and meta-analyses (PRISMA) flow sheet
Year
2013
2013
2013
2012
2013
2013
2013
2013
2013
2012
2013
Study
Arshad [15]
Bassiouny [16]
Bernard [17]
Ellis [18]
Gadiyaram [19]
Haines [20]
Ichiki [21]
Imamura [22]
Kaiser [23]
Kaseno [24]
Khan [25]
ACC
Circulation Journal
JICE
JICE
PACE
JICE
HRS
HRS
ACC
Circ EP
HRS
Publication/ meeting
50, 66
110, 101
122, 135
101, 126
30, 180
202, 202
54, 128
56.3, -
–
58, 64
61, 62
57, 60
60.2, 59.7
62.7
–
(63, 63)b, 67
(155, 75)b, 44 61, 110
59, 63
60.7 ± 10
Mean age [years; (NOACs, W)]
376, 623
298, 153
Sample size (NOACs, W)
Table 1 Characteristics of included studies
39
–
36, 32
25, 30
17, 22
26, 31
24, 24
–
–
25, 27
28
Females,% (NOACs, W)
–
–
69, 47
44, 51
70, 30
55, 50
–
–
(46, 57)b, 50
Abl.
Abl.
LAA abl.
Abl.
Abl.
Abl.
Abl.
Abl.
Abl.
Abl.
Abl.
67a
57, 55
Type of procedure
PAF (%; NOACs, W)
1.06, -
–
1.2 ± 1, 1.6 ± 1
0.9 ± 0.9, 1.1 ± 1.0
1.1 ± 1.1, 1.0 ± 1.0
1.6 ± 1.3, 1.9 ± 1.4c
–
1.2 ± 0.2
–
–
1.3 ± 1.0
CHADS2 score (NOACs, W)
–
–
–
0.7 ± 0.8, 1.0 ± 0.9
–
–
–
–
–
–
2.8 ± 1.0
HAS-BLED score (NOACs, W)
D 150
D 110
D 150
D 110/D 150 depending on patient’s condition
D 110–13 patients, D 150–17
D 150 (1 patient received D 110)
R
D 150, R
D 150, R
D 150
D 150
NOACs: drug, dose (mg)
Warfarin was stopped 3 days before the procedure and unfractionated heparin was administered Held 12–24 h before and restarted 3 h after the procedure
Last dose held 24 h prior to the procedure and restarted 6 h after sheath removal
Held on the morning of the procedure, and resumed on the next morning
Uninterrupted
Uninterrupted
Uninterrupted
Uninterrupted Discontinued only on the morning of the procedure, resumed from the evening
Held 24–30 h pre-procedure and restarted 4–6 h after hemostasis was achieved
Therapeutic pre-procedure INR in 80%, remaining bridged with lovenox
Uninterrupted
Subtherapeutic INR bridged with heparin
Uninterrupted
Uninterrupted
Uninterrupted
Warfarin
17% received D within 12 h before the procedure, D resumed within 24 h
Held 2 days before ablation, one dose of lovenox 6 h after hemostasis was achieved and R was resumed the next day
Held 12–48 h pre-procedure, resumed within 4–24 h after sheath pull
Held within 24 h pre-procedure and restarted within 24 h post-procedure
1–2 doses held before procedure resumed at conclusion of the procedure
Held 12 h pre-procedure and resumed on post-procedure night
NOACs held
Cardiol Ther (2016) 5:85–100 89
2013
Nin [31]
2014
2013
Mohajer [30]
Snipelisky [41]
2012
Mendoza [29]
2012
2013
Maddox [28]
Snipelisky [32]
2014
Lakkireddy [38]
2012
2013
Lakkireddy [27]
2012
2012
Konduru [37]
Pavaci [39]
2013
Kim [26]
Rowley [40]
Year
Study
HRS
JICE
HRS
ESC
PACE
Canadian Journal of Cardiology
HRS
JCE
JACC
JACC
JICE
Heart Rhythm
Publication/ meeting
Table 1 continued
27, 27
56, 25, 48
31, 125
113, 169
–
60.6, 64.6
63
–
61, 61
60, 63
43, 95
45, 45
62.9, 64.0
62.3, 62.5
63, 63
60.4, 60.3
56.6, 60.9
61, 61
Mean age [years; (NOACs, W)]
60, 58
212, 251
321, 321
145, 145
24, 52
191, 572
Sample size (NOACs, W)
–
19.4, 25.6
–
–
16, 20
–
10, 12
24, 33
31, 31
21, 21
21, 33
20, 26
Females,% (NOACs, W)
–
68, 46
–
–
34, 32
69.8, 41.1
63, 57
49, 49
57, 57
21, 44
53, 48
PAF (%; NOACs, W)
Abl.
Abl.
Abl.
Abl.
Abl.
Abl.
Abl.
Abl.
Abl.
Abl.
Abl.
Abl.
Type of procedure
–
0.84, 1.22
1.3 ± 1
–
–
0.6 ± 0.7, 0.9 ± 0.9
1.32, 1.29
0.92 ± 0.88, 0.92 ± 0.85
1.16 ± 1.0, 1.18 ± 1.0
1.6 ± 1.4, 1.5 ± 1.3c
–
1.0 ± 0.9, 1.1 ± 1.0
CHADS2 score (NOACs, W)
–
–
–
–
–
–
1.47, 1.63
1.47 ± 0.9, 1.70 ± 1.0
1.2 ± 0.9, 1.1 ± 0.9
–
1.0 ± 0.9, 1.1 ± 1.0
HAS-BLED score (NOACs, W)
D, R
D 150
–
–
D 110
D 150 (D 110 in 3 patients)
D 150
D 150
R 15, 20
D 150
D 150
D 150
NOACs: drug, dose (mg)
–
–
Held the dose on the morning of the procedure
Last dose the day before AF ablation and typically restarted the day following ablation
–
Uninterrupted
Bridged with enoxaparin
–
Uninterrupted
Uninterrupted
Held 24 h prior to procedure
Held on morning of the procedure and resumed 4 h after hemostasis
Uninterrupted
Uninterrupted
Uninterrupted
Uninterrupted
Uninterrupted
Uninterrupted
Warfarin
Held only the morning of the procedure and resumed immediately after sheath removal
Morning dose on the day of the ablation procedure; post-procedural dabigatran was administered on the evening of the procedure
Uninterrupted
Held on the morning of the procedure, resumed within 3 h after hemostasis
Continued without interruption (first 11 patients) or held 2 doses immediately prior to the procedure (last 13 patients). D was continued the evening following the procedure
Held after the morning dose on the day before the procedure and resumed 4 h after hemostasis was achieved
NOACs held
90 Cardiol Ther (2016) 5:85–100
Clinical Drug Inv.
106, 106
79, 15, 45
70, 70
89, 98, 114
Sample size (NOACs, W)
60, 61
61
66
59, 60, 62.9
Mean age [years; (NOACs, W)]
25, 24
25
30
42, 34, 33
Females,% (NOACs, W)
65, 64
–
73
70, 81, 64
PAF (%; NOACs, W)
Abl.
Abl.
Abl.
Abl.
Type of procedure
1.8 ± 1.6, 1.7 ± 1.6
–
–
–
CHADS2 score (NOACs, W)
–
–
–
–
HAS-BLED score (NOACs, W)
D 110 (36), D 150 (70)
D, R
R 10, 15
D, R
NOACs: drug, dose (mg)
– Uninterrupted
Held on the day of procedure, resumed 3 h after the completion
Uninterrupted
Uninterrupted
Warfarin
–
Uninterrupted
The last dose of D was given the morning 1 day prior to the procedure, and the last dose of R was given the evening 2 days prior. Bridged with heparin NOAC was resumed at 8:00 a.m. on the morning after the procedure
NOACs held
a
Abl. ablation, ACC American College of Cardiology, D dabigatran, ESC European Society of Cardiology, HRS Heart Rhythm Society, INR international normalized ratio, NOACs novel oral anticoagulants, PAF paroxysmal atrial fibrillation, R rivaroxaban, W warfarin Total PAF in study cohort b NOACs (dabigatran, rivaroxaban) c CHADS2-Vasc score
2013
Yamaji [36]
HRS
HRS
2014
2014
Tao [34]
Ueno [35]
JICE
2014
Stepanyan [33]
Publication/ meeting
Year
Study
Table 1 continued
Cardiol Ther (2016) 5:85–100 91
Cardiol Ther (2016) 5:85–100
92
Fig. 2 Funnel plot to assess publication bias for a the composite endpoint of stroke, TIA, peripheral arterial embolism, or silent cerebral lesions on MRI b major bleeding for AF ablation (OR: 0.90, 95% CI: 0.34–2.41, P = 0.84). Sensitivity analysis was performed by
Exclusion sensitivity analysis including only symptomatic thromboembolic complications
using a fixed effects analysis method. Effect size
(stroke, TIA, and peripheral arterial embolism)
did not change with fixed effects analysis. To assess whether the time of holding NOAC
was performed after omitting studies reporting silent cerebral lesions on MRI. Sensitivity
affected the composite endpoint, exclusion sensitivity analysis was performed by
analysis did not reveal any difference between NOACs and warfarin (OR: 1.48, 95% CI:
including only those studies in which an
0.75–2.91, P = 0.25; Fig. 4). Subgroup analysis
NOAC was held on the day of AF ablation. This analysis showed that dabigatran was
did not show any increased risk with either dabigatran or rivaroxaban for AF ablation (OR:
associated with increased risk of the composite endpoint (OR: 2.40, 95% CI: 1.10–5.22,
1.69, 95% CI: 0.81–3.51, P = 0.16 and OR: 0.70, 95% CI: 0.12–4.04, P = 0.69, respectively;
P = 0.03).
Fig. 4).
On
the
other
hand,
use
of
rivaroxaban did not increase the risk of thromboembolic complications (OR: 1.1, 95% CI 0.30–4.79, P = 0.79). In four studies [18, 20, 22, 40], heparin was used for bridging during the periprocedural period for anticoagulation. To assess whether uninterrupted warfarin affected the composite endpoint, sensitivity analysis was conducted by omitting studies in which heparin bridging was used. Pooled analysis of the remaining studies revealed that dabigatran was associated with increased risk of the composite endpoint (OR: 1.81, 95% CI: 1.02–3.19, P = 0.04) whereas rivaroxaban therapy did not increase the risk of thromboembolic complications (OR: 0.90, 95% CI: 0.34–2.41, P = 0.84).
Major Bleeding There was no significant heterogeneity across the studies (v2 = 23, degrees of freedom = 23; P = 0.46; I2 = 0%). Major bleeding events were similar with NOACs and warfarin for AF ablation (OR: 0.91, 95% CI: 0.62–1.34, P = 0.63; Fig. 5). Pooled analysis of studies in which uninterrupted warfarin was utilized for periprocedural anticoagulation did not show any significant difference in major bleeding between NOACs and warfarin (OR: 0.93, 95% CI: 0.58–1.50, P = 0.77).
Cardiol Ther (2016) 5:85–100
93
Fig. 3 Forest plot showing sub group analysis of the composite endpoint of stroke, TIA, peripheral arterial embolism, or silent cerebral lesions on MRI based on type of new oral anticoagulants
Major Bleeding-Type of NOACs Subgroup analysis, based on the type of NOAC, revealed similar major bleeding with dabigatran and warfarin when used for AF ablation (OR:
0.99, 95% CI: 0.62–1.57, P = 0.96). There was no significance difference in major bleeding between rivaroxaban and warfarin (OR: 0.60, 95% CI: 0.25–1.45, P = 0.25).
Cardiol Ther (2016) 5:85–100
94
Fig. 4 Forest plot showing sub group analysis of symptomatic thromboembolic events (stroke, TIA, and peripheral arterial embolism) based on type of new oral anticoagulants
DISCUSSION
embolism, or silent cerebral lesions on MRI compared to warfarin. However, the risk of
There are three major findings of this study. First, the use of dabigatran for periprocedural
symptomatic
thromboembolic
events
with
anticoagulation for AF ablation is associated
dabigatran therapy anticoagulation with
is similar to warfarin. Second,
with an increased risk of the composite endpoint of stroke, TIA, peripheral arterial
rivaroxaban is not associated with increased risk of the composite endpoint when compared
Cardiol Ther (2016) 5:85–100
95
Fig. 5 Forest plot showing sub group analysis of bleeding events based on type of new oral anticoagulants to warfarin. Third, dabigatran and rivaroxaban are comparable to warfarin in terms of bleeding
Rhythm Society (HRS) guidelines recommend anticoagulation in patients with AF with high
complications.
risk for thromboembolic events identified by
Current American Heart Association (AHA)/ American College of Cardiology (ACC)/Heart
the CHA2DS2-VASc score [43]. Recent meta-analyses presented mixed data regarding
Cardiol Ther (2016) 5:85–100
96
the
role
of
dabigatran
therapy
for
sample size of the rivaroxaban subgroup (548
periprocedural anticoagulation for AF ablation
vs. 2451 in the dabigatran subgroup).
[11–13, 44]. Our study suggests dabigatran therapy for AF ablation may be associated with
Silent cerebral infarcts may be associated with neurocognitive impairment and/or gait
increased thromboembolic risk. Shurrab et al. [12] and Bin Abdulhak et al. [44] reported no
abnormality [47]. A recent retrospective study evaluating the incidence of silent cerebral
significant difference in thromboembolic events
lesions
between dabigatran and warfarin therapy. Sardar et al. [11] and Steinberg et al. [13]
edoxaban suggested an increased risk of silent cerebral lesions with dabigatran [48]. This is
observed that periprocedural dabigatran use may be associated with increased risk of
consistent with the findings of our study, which showed potentially higher risk of silent cerebral
neurological events. In these meta-analyses,
lesions with dabigatran. The majority (91.8%)
silent cerebral lesions on MRI were not included as one of the primary outcomes. Our
of the cerebral lesions noted on initial MRI were not seen on following MRI suggesting that only
study is the first pooled analysis to include and evaluate the incidence of silent cerebral lesions
a few lesions develop into chronic cerebral lesions [48]. This study was limited by the
on MRI. Gaita et al. [45] reported an incidence
retrospective and non-randomized nature of
of cerebral microthromboembolism of 14% with warfarin therapy for AF ablation and
the study. Prospective randomized clinical studies are needed to evaluate the incidence of
increased risk of cerebrovascular events was related to use of cardioversion. Our pooled
cerebral microthromboembolism with NOACs and to determine clinical characteristics which
analysis included silent cerebral lesions on MRI as one of the primary outcomes and it
increase the likelihood microthromboembolism.
revealed that dabigatran therapy is potentially
Our
with
study
different
is
NOACs
consistent
including
of
cerebral
with
other
associated with a higher risk of silent cerebral lesions on MRI. Exclusion sensitivity analysis
meta-analyses which revealed NOACs are associated with similar bleeding risk when
after omitting studies reporting silent cerebral lesions on MRI did not show any significant
compared to warfarin [11–13, 44]. Subgroup analysis based on type of anticoagulant did not
difference in thromboembolic events between
show any difference between the NOACs.
dabigatran and warfarin therapy for AF ablation. Ueno et al. [46] showed that during
Limitations
AF ablation, pro-thrombotic factors are activated more with dabigatran than warfarin.
The studies included in the meta-analysis had
Ichiki et al. [21] observed an increased risk of asymptomatic cerebral thromboembolic events with dabigatran therapy for AF ablation.
differences in their study protocol. We could not study the risk of thromboembolic and bleeding events based on the dose of NOACs
Conversely, Kaseno et al. [24] reported similar cerebral microthromboembolism with
(110, 150 mg of dabigatran; 10, 15, 20 mg of rivaroxaban). There was significant
dabigatran. Our analysis did not show any
heterogeneity in different protocols in terms of number of doses of NOACs held prior to the
difference in the composite endpoints between rivaroxaban and warfarin therapy for AF ablation. This analysis may be limited by small
ablation, bridging therapy with heparin, and timing of resumption of NOACs after the
Cardiol Ther (2016) 5:85–100
97
procedure. Definitions for safety and efficacy
William R. Lewis have no conflict of interest
outcomes, and baseline characteristics of the
relevant to the topic in discussion.
patients varied across the studies. The majority of the studies were observational studies without any randomization or propensity matching. Apixaban is being increasingly used in clinical practice for AF ablation. Studies evaluating the safety and efficacy of periprocedural anticoagulation with apixaban and edoxaban for AF ablation were not included in the pooled analysis [48–50] as these studies were published after the completion of the literature search in May 2014.
Compliance with Ethics Guidelines. This article
is
based
on
previously
conducted
studies and does not involve any new studies of human or animal subjects performed by any of the authors. Open Access. This article is distributed under the terms of the Creative Commons AttributionNonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4. 0/), which permits any noncommercial use, distribution, and reproduction in any medium,
CONCLUSIONS
provided you give appropriate credit to the
Dabigatran and rivaroxaban are comparable to
original author(s) and the source, provide a link to the Creative Commons license, and indicate
warfarin in terms of bleeding complications. However, dabigatran therapy is potentially
if changes were made.
associated with a higher risk of cerebral lesions on MRI. The results of study should be considered as hypothesis-generating and
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